SYSTEMATIC REVIEW
published: 04 June 2018
Edited by:
Sandor Kerpel-Fronius,
Semmelweis University, Hungary
Reviewed by:
Leon Farhy,
University of Virginia, United States
Brian Godman,
Karolinska Institutet (KI), Sweden
*Correspondence:
Zhi-Chun Gu
guzhichun213@163.com
Xiao-Yan Liu
liuxiaoyanrenji@163.com
† These authors have contributed
equally to this work and co-first
authors.
Specialty section:
This article was submitted to
Pharmaceutical Medicine and
Outcomes Research,
a section of the journal
Frontiers in Pharmacology
Received: 01 March 2018
Accepted: 14 May 2018
Published: 04 June 2018
Citation:
Shi F-H, Li H, Cui M, Zhang Z-L,
Gu Z-C and Liu X-Y (2018) Efficacy
and Safety of Once-Weekly
Semaglutide for the Treatment of Type
2 Diabetes: A Systematic Review and
Meta-Analysis of Randomized
Controlled Trials.
Front. Pharmacol. 9:576.
doi: 10.3389/fphar.2018.00576
Frontiers in Pharmacology | www.frontiersin.org
doi: 10.3389/fphar.2018.00576
Efficacy and Safety of Once-Weekly
Semaglutide for the Treatment of
Type 2 Diabetes: A Systematic
Review and Meta-Analysis of
Randomized Controlled Trials
Fang-Hong Shi 1† , Hao Li 2† , Min Cui 1 , Zai-Li Zhang 1 , Zhi-Chun Gu 1* and Xiao-Yan Liu 1*
1
Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China, 2 Department
of Pharmacy, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
Background: Semaglutide, a newly once-weekly glucagon like peptide-1 (GLP-1)
receptor agonist, has showed a favorable effect on glycaemic control and weight
reduction in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to
evaluate the clinical efficacy and safety of semaglutide in T2DM.
Methods: A comprehensive searching was performed for Phase III randomized
controlled trials (RCTs) which reported the efficacy and safety data of semaglutide and
other therapies. The efficacy data expressed as weight mean difference (WMD) and the
safety data expressed as risk ratios (RRs) were calculated by employing random-effects
model. Heterogeneity was assessed through I2 test, and subgroup analyses were
performed by different control groups, dosage of semaglutide, and durations of follow up.
Results: 9 RCTs including 9,773 subjects met the inclusion criteria. For efficacy,
compared with other therapies, semaglutide resulted in a significant reduction in
glycosylated hemoglobin (weight mean difference, WMD: −0.93%, 95% CI: −1.24
to −0.62, P < 0.001), fasting plasma glucose (WMD: −1.15 mmol/L, 95% CI: −1.67
to −0.63, P < 0.001), mean self-monitoring of plasma glucose (WMD: −1.19 mmol/L,
95% CI: −1.68 to −0.70, P < 0.001), body weight (WMD: –3.47 kg, 95% CI: −3.96
to −2.98, P < 0.001), body mass index (WMD: –1.25 kg/m2 , 95% CI: −1.45 to −1.04,
P < 0.001), systolic blood pressure (WMD: −2.55 mmHg, 95% CI: −3.22 to −1.88,
P < 0.001), with the exception of negative result of diastolic blood pressure (WMD:
−0.29 mmHg, 95% CI: −0.65 to 0.07, P = 0.113) and increased impact on pulse rate
(WMD: −2.21, 95% CI: 1.54 to 2.88, P < 0.001). The results were consistent across the
key subgroups. For safety, semaglutide did not increase the risk of any adverse events,
hypoglycemia and pancreatitis, but induced a higher risk of gastrointestinal disorders
when compared with other therapies (RR: 1.98, 95%CI: 1.49 to 2.62, P < 0.001).
1 June 2018 | Volume 9 | Article 576
Shi et al. Efficacy and Safety of Semaglutide in Type 2 Diabetes

Conclusion: Semaglutide was effective and acceptable in patients with T2DM except
for a high risk of gastrointestinal disorders. The capacity of glycaemic and body weight
control of semaglutide appeared more effective than other add-on therapies including
other GLP-1 receptor agonists of exenatide release and dulaglutide.

Keywords: type 2 diabetes, glucagon-like peptide-1 receptor agonists, semaglutide, randomized controlled trials,
meta-analysis

INTRODUCTION albumin affinity (Lau et al., 2015). The molecular modification

Type 2 diabetes mellitus (T2DM) is a complex and progressive
disease due to a progressive loss of β-cell insulin secretion
frequently on the basis of insulin resistance that manifests
clinically as hyperglycemia (Inzucchi et al., 2015). Despite various
medications are now available for the treatment of T2DM, it
remains a challenge to select anti-diabetic agents that come with
a good balance between efficacy and safety.
Metformin is generally recommended as the first-line
therapeutic agent in T2DMs with lifestyle changes according
to the American Diabetes Association (ADA) and European
Association for the Study of Diabetes (ADA/EASD).(Inzucchi
et al., 2012).
When lifestyle changes and maximally tolerable dose
of metformin fail to control hyperglycemia, other anti-
hyperglycemic drugs are necessary to better control of
glucose including oral antihyperglycemic drugs (sulfonylureas,
thiazolidinedione, DPP4 inhibitors, alpha glucosidase inhibitors
etc.) and injectable anti-hyperglycemic drugs (insulin, Glucagon-
like peptide-1 receptor agonists etc.) (Koro et al., 2004; Doggrell,
2018). Of note, the effect of long-term glycemic control may not
be maintained owing to gradually declined beta cell function or
subsequently increased cardiovascular risk (Turner et al., 1999).
Therefore, the selection of anti-hyperglycemic drugs balancing
the efficacy and safety is needed.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a
kind of secreted peptide that release from neuroendocrine
intestinal L-cells, are recently recommended by American
Diabetes Association/European Association for the Study of
Diabetes (ADA/EASD) as a second-line treatment when first-line
treatment (mainly metformin monotherapy) fails to achieve well
controlled glucose. Owing to their efficacy on glycemic control
and reduction of body weight and blood pressure (BP), with a low
risk of hypoglycemia, GLP-1RAs are extensively used in diabetes
patients (Inzucchi et al., 2012; Dugan, 2017).
Semaglutide, a newly subcutaneous and long acting GLP-1
RA with 94% structural homology to native GLP-1, has been
approved by the United States Food and Drug Administration
(FDA) on December 5, 2017, as an adjunct to diet and exercise
for the treatment of T2DM (Lau et al., 2015; Dhillon, 2018).
Semaglutide has three modified GLP-1 peptides that contains
two amino acid substitutions as compared to native GLP-1
(Aib8, Arg34) and derivatized at lysine 26. Semaglutide is similar
to liraglutide in structure, but more resistant property than
liraglutide by structural modifications, making it less susceptible
to degradation by enzyme dipeptidyl peptidase-4 and more
of semaglutide brings about a long half-life of 165 h, which
may represent a preferably once-weekly GLP-1 analog (Kapitza
et al., 2015). Although semaglutide has been evaluated in several
randomized trials, the overall evaluation of semaglutide is urgent.
We thus conducted a systemic review and meta-analysis to
present a comprehensive picture on the efficacy and safety of
semaglutide in patients with T2DM.
MATERIALS AND METHODS
Study Design
This meta-analysis was conducted in accordance to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines and was conducted following a priori
established protocol (PROSPERO: CRD42018084958) (Moher
et al., 2010). Ethical approval is not required because this
is a systemic review study. A comprehensively systematic
search of Medline, Embase, and the Cochrane library was
conducted from inception to Feb 24th, 2018 without language
restriction. Additionally, unpublished trials were identified from
the “ClinicalTrials.gov” website. References of all pertinent
articles were further scrutinized to ensure that all relevant studies
were identified. For the topic of “type 2 diabetes,” the following
key terms were used for searching: “type 2 diabetes” or “type 2
diabetes mellitus”. For the topic of “semaglutide,” we included
the following terms: “semaglutide” or “NN9936” or “NN9934” or
“NN9935” or “ozempic.” For the topic of “randomized controlled
trials (RCTs),” the terms used were: “clinical trial” or “controlled
clinical trial” or “randomized controlled trial.” Finally, we used
the Boolean operator “AND” to combine three comprehensively
searching topics. Two reviewers (Fang-Hong Shi and Hao Li)
independently searched the databases to identify all potentially
eligible studies, and all disagreements were resolved by consensus
or by consulting a third author (Zhi-Chun Gu).
Inclusion Criteria and Study Selection
All Phase III RCTs assessing the efficacy and safety of semaglutide
in T2DM were considered as a potentially eligible paper. The
predetermined study inclusion criteria were: (1) RCTs; (2)
adult patients had T2DM; (3) compared semaglutide with other
therapies (anti-diabetic therapy or placebo); (4) reported the
interested efficacy data including estimated treatment difference
about glycemic control, weight control, and blood pressure and
pulse rate; (5) reported safety data including adverse events
(AEs) with varying degrees and AEs occurring in ≥ 5% patients

Frontiers in Pharmacology | www.frontiersin.org 2 June 2018 | Volume 9 | Article 576

Shi et al.
according to predetermined terms or clinical significance; (6) the
duration of follow up should be more than 24 weeks.
Data Extraction
Two investigators (Fang-Hong Shi and Hao Li) screened the
titles and abstracts of retrieved citations independently to identify
potentially eligible trials. Following data were extracted from the
eligible trials: first author’s name, year of publication, number
of study patients, baseline patient characteristics, related efficacy
and safety data.
Quality Assessment and Bias Assessment
Two investigators (Fang-Hong Shi and Hao Li) evaluated the
methodological quality of included randomized trials according
to the Cochrane Collaboration Risk of Bias Tool, which includes
random sequence generation, allocation concealment, masking,
incomplete outcome data, selective reporting, and other bias
(Higgins et al., 2011). Furthermore, we also assessed the
background medication administration and funding sources.
Any disagreement was settled by discussing with the third author
(Zhi-Chun Gu). Potential publication bias was evaluated by
visually inspecting funnel plots as well as quantitative analysis of
Begg test and Egger test (Egger et al., 1997).
Data Analysis
The estimates of meta-analysis were derived and presented in
forest plots by using STATA version 12.0 (STATA Corporation,
College Station, TX, USA) (Jaïs et al., 2008). Continuous variables
were expressed as weight mean difference (WMD) with their
95% confidence intervals (95% CIs), and dichotomous data
were reported as risk ratios (RRs) with 95% CIs. The random-
effects model was used to calculate the overall estimated effects.
Heterogeneity, which measures the percentage of total variation
between studies, was tested through the I2 test (Chen et al., 2017).
Subgroup analyses were performed by different control groups
(placebo, sitagliptin, insulin glargine, other GLP-1 RAs, and other
oral anti-diabetic drug), dosage of semaglutide (0.5 or 1.0 mg
weekly) and duration of follow up. We conducted a sensitivity
analysis to evaluate the influence of each individual study by
omitting one study at a time as well as the impact after removing
the placebo-controlled studies. P < 0.05 indicated a statistically
significant difference.
RESULTS
Study Evaluation
A total of 457 initially relevant publications were identified. Of
these, 448 records were excluded through screening title and
abstract by different reasons (Among these records, 10 RCTs were
excluded which were listed in Table S1). Finally, 9 studies were
identified for the final analysis (including 1 abstract) (Figure 1)
(Conway et al., 2016; Marso et al., 2016; Ahrén et al., 2017; Aroda
et al., 2017; Sorli et al., 2017; Ahmann et al., 2018; Kaku et al.,
2018; Pratley et al., 2018; Seino et al., 2018). The characteristics of
the included RCTs were represented in Table 1. Publication year
varied from 2016 to 2018, and the trial duration ranged from 30 to
104 weeks. In total, 9,773 participants were included, consisting
of 5,774 patients in semaglutide group and 3,999 patients in other
Frontiers in Pharmacology | www.frontiersin.org
Efficacy and Safety of Semaglutide in Type 2 Diabetes
therapies group. Regarding comparators in included studies,
3 studies (4,550 patients) received placebo, 2 studies (1,533
patients) received sitagliptin, 2 studies (2,008 patients) received
other GLP-1 RAs (exenatide release or dulaglutide), 1 study
(1,082 patients) received insulin glargine and 1 study (600
patients) received other oral antidiabetic drugs. Among included
9 RCTs, 5 studies involving 3,998 patients were open label studies
(Aroda et al., 2017; Ahmann et al., 2018; Kaku et al., 2018; Pratley
et al., 2018; Seino et al., 2018). All trials satisfied all bias tool items
with the exception of blind method. Thus, the overall quality of
included trials was moderate to high (Table S2).
Efficacy Analysis
Glycemic Control (Glycosylated Hemoglobin%,
Fasting Plasma Glucose, Self-Monitoring of Plasma
Glucose and Postprandial Self-Monitoring of Plasma
Glucose)
Figure 2 summarized the overall efficacy results of semaglutide,
and Table S3 presented the corresponding subgroup results.
For glycosylated hemoglobin (HbA1c%), the result showed that
semaglutide significantly decreased the HbA1c% level when
compared with other therapies (WMD: −0.93%, 95% CI: −1.24
to −0.62, P < 0.001). As for fasting plasma glucose (FPG), the use
of semaglutide was associated with a lower FPG concentration
compared with other therapies (WMD: −1.15 mmol/L, 95%
CI: −1.67 to −0.63, P < 0.001). Regarding self-monitoring of
plasma glucose (SMPG), which reflects average level of glycemic
control after 7–8 times testing a day, has been recommended in
the process of self-management in diabetes patients. The results
showed a significantly decrease in SMPG (WMD: −1.19 mmol/L,
95% CI: −1.68 to −0.70, P < 0.001) as well as postprandial
self-monitoring of plasma glucose (PSMPG) (WMD: −0.43
mmol/L, 95% CI: −0.57 to −0.30) with semaglutide vs. other
therapies. The considerable heterogeneity was detected across
above outcomes (I2 = 92.6% for HbA1c%, I2 = 90.8% for FPG,
I2 = 92.9% for SMPG, and I2 = 55.5% for PSMPG).
Weight Control (Body Weight, Body Mass Index, and
Waist Circumference)
The results of weight control were presented in Figure 2 and
Table S3. With regard to body weight, semaglutide use was
associated with a significantly reduced body weight than other
therapies (WMD: −3.47 kg, 95% CI: −3.96 to −2.98, P < 0.001).
Similarly, both body mass index (BMI) (WMD: −1.25 kg/m2 ,
95% CI: −1.45 to −1.04, P < 0.001) and waist circumference
(WMD: −2.59 cm, 95% CI: −3.09 to −2.08, P < 0.001) showed
a significant reduction in semaglutide when compared to other
therapies. No significant heterogeneity was observed within
included studies (I2 = 17.6% for body weight, I2 = 30.5% for
BMI, and I2 = 30.7% for waist circumference).
Blood Pressure and Pulse Rate
For blood pressure control, systolic blood pressure (SBP), but
not diastolic blood pressure (DBP) (WMD: −0.29 mmHg, 95%
CI: −0.65 to 0.07, P = 0.113), revealed a significant reduction
with semaglutide than other therapies (WMD: −2.55 mmHg,
95% CI: −3.22 to −1.88, P < 0.001). Unlike blood pressure, the
use of semaglutide showed a significantly elevated pulse rate as
3 June 2018 | Volume 9 | Article 576
Shi et al.
FIGURE 1 | Flow diagram for the selection of eligible randomized controlled trials. RCT indicates randomized controlled trial.
compared with other therapies (WMD: 2.21 bpm, 95% CI: 1.54
to 2.88, P < 0.001), with moderate heterogeneity within studies
(I2 = 67.6).
Safety Analysis
The following AEs were included for comparative analysis
of safety and tolerability: AEs with varying degrees and AEs
occurring in ≥ 5% patients based on predetermined terms or
clinical significance. Finally, 22 AEs were selected, and results
were presented in Table 2 and Table S4. The most significant
results of the data from analyses were discussed next.
All included studies reported different degrees of AEs. The
data showed that semaglutide did not increase the risk of any
AEs (RR: 1.04, 95% CI: 0.99 to 1.09, P = 0.147), serious AEs
(RR: 0.93, 95% CI: 0.86 to 1.01, P = 0.084), fatal AEs (RR: 0.90,
95% CI: 0.56 to 1.47, P = 0.678), moderate AEs (RR: 1.01, 95%
CI: 0.90 to 1.15, P = 0.833), and mild AEs (RR: 1.08, 95% CI:
0.96 to 1.22, P = 0.194), with the exception of AEs leading to
premature treatment discontinuation (RR: 2.07, 95% CI: 1.58 to
2.73, P < 0.001).
The incidence of gastrointestinal disorders was 42.9% (2193
of 5107) in the semaglutide group, while that was 29.6% (1026
of 3461) in the other therapies group. Thus, the presence of
gastrointestinal disorders was considered as the most common
AEs, and the pooled data showed a significantly higher risk with
semaglutide than other therapies (RR = 1.98, 95% CI: 1.49 to
2.62, P < 0.001).
The total incidence of hypoglycemia was 12.8% (411 of
3,197) in patients treated with semaglutide, while that was
14.0% (367 of 2603) in other therapies group. In SUSTAIN 6
Frontiers in Pharmacology | www.frontiersin.org
Efficacy and Safety of Semaglutide in Type 2 Diabetes
study, the incidence of hypoglycemia was 22.4% (369 of 1648)
in semaglutide group and 21.2% (350/1649) in placebo group,
respectively (Marso et al., 2016). Accordingly, the pooled data
failed to show a significantly increased risk of hypoglycemia in
patients taking semaglutide than those receiving other treatment
(RR: 1.07, 95% CI: 0.94 to 1.21, P = 0.317).
Pancreatitis occurred with the incidence of 0.3% (15 of 4422)
and 0.4% (12 of 2831) in semaglutide group and in other therapies
group, respectively. No significantly higher risk was observed
with semaglutide vs. other therapies (RR: 0.82, 95% CI: 0.36 to
1.88, P = 0.641).
The incidence of nasopharyngitis was slightly higher in
semaglutide as compared to other therapies (10.9% vs.10.7%),
with a corresponding RR of 0.86 (95%CI: 0.74 to 0.99, P = 0.04).
No statistical difference was found in the incidence of other
known AEs in terms of cardiovascular disorders (RR: 0.88, 95%
CI: 0.78 to 1.01, P = 0.066), neoplasms (RR: 1.07, 95% CI: 0.78 to
1.46, P = 0.673), and nervous system disorders (RR: 1.08, 95% CI:
0.68 to 1.71, P = 0.75) between semaglutide and other therapies.
Subgroup and Sensitivity Analysis
The results of semaglutide by different dosage (0.5 mg or 1.0 mg)
and duration of follow up (< 30 weeks or more than 30 weeks)
were consistent with the primacy analysis in terms of efficacy and
safety (Tables S3, S4), some differences are discussed next.
Considering glycemic control by different treatment, the
use of semaglutide significantly reduced HbA1c%, FPG, SMPG
as well as PSMPG as compared to other therapies (placebo,
sitagliptin, other GLP-1 RAs, and other oral anti-diabetic drug)
except for FPG (WMD: −0.27 mmol/L, 95% CI: −0.94 to 0.41,
4 June 2018 | Volume 9 | Article 576
 Shi et al.

TABLE 1 | Demographic and other baseline characteristics.

Study Sorli C Ahrén B Ahmann AJ Aroda VR Marso SP Richard EP Seino Y Kaku K

(SUSTAIN1) (SUSTAIN2) (SUSTAIN3) (SUSTAIN4) (SUSTAIN6) (SUSTAIN7) (SUSTAINTM ) (SUSTAINTM )

NCT number NCT02054897 NCT01930188 NCT01885208 NCT02128932 NCT01720446 NCT02648204 NCT02254291 NCT02207374
Year 2017 2017 2018 2017 2016 2018 2018 2018
Follow up (weeks) 30 56 56 30 104 40 30 56
Background DE MET+TZD OAD MET±SU AHA MET DE±OAD DE or OAD
Variable SEM SEM PLA SEM SEM SIT SEM EXER SEM SEM GLA SEM SEM PLA SEM SEM DUL SEM SEM SIT SEM SEM OAD

Frontiers in Pharmacology | www.frontiersin.org

Dosage (mg) 0.5 1.0 N/A 0.5 1.0 N/A 1.0 2.0 0.5 1.0 N/A 0.5 1.0 N/A 0.5 1.0 N/A 0.5 1.0 N/A 0.5 1.0 N/A
Participants 128 130 129 409 409 407 404 405 362 360 360 826 822 1649 301 300 598 103 102 103 239 241 120
Mean age (year) 54.6 52.7 53.9 54.8 56.0 54.6 56.4 56.7 56.5 56.7 56.2 64.6 64.7 64.6 56.0 55.0 56.0 58.8 58.1 57.9 58.0 58.7 59.2
HbA1C
% 8.1 8.1 8.0 8.0 8.0 8.2 8.4 8.3 8.1 8.3 8.1 8.7 8.7 8.7 8.3 8.2 8.2 8.2 8.0 8.2 8.0 8.1 8.1
mmol/mol 64.9 65.3 63.4 64.1 64.4 65.8 67.9 67.7 65.4 66.6 65.4 NK NK NK 67.5 65.7 66.2 NK NK NK 64.4 65.5 65.1
mean duration of 4.8 3.6 4.1 6.4 6.7 6.6 9.0 9.4 7.8 9.3 8.6 14.3 14.1 13.6 7.7 7.0 7.4 8.0 7.8 8.1 8.1 9.4 9.3
diabetes (years)
Body weight (kg) 89.8 96.9 89.1 89.9 89.2 89.3 96.2 95.4 93.7 94.0 92.6 91.8 92.9 91.9 96.4 95.6 94.5 67.8 70.8 69.4 71.0 71.7 72.2
BMI (kg/m2 ) 32.5 33.9 32.4 32.4 32.5 32.5 34.0 33.6 33.1 33.0 33.0 32.7 32.9 32.8 33.7 33.6 33.4 25.1 26.1 25.1 26.2 26.4 26.7

5
eGFR (MDRD; ml/min 95.9 100.9 100.2 97.0 97.0 98.0 100.5 100.5 97.9 98.0 99.7 NK NK NK 96.0 96.0 96.0 NK NK NK 101.4 101.6 102.0
per 1.73 m2 )
SEX (%)
Female 53 38 46 49 50 49 46 44 46 49 46 40 37 40 44 46 45 23 27 21 31 28 26
Male 47 62 54 51 50 51 54 56 54 51 54 60 63 60 56 54 55 77 73 79 69 72 74
ETHNIC ORIGIN (%)
Hispanic or latino 27 35 28 17 16 18 23 26 17 21 22 16 15 15 10 10 13 NK NK NK NK NK NK
Not Hispanic or latino 73 65 72 83 84 82 77 74 83 79 78 84 85 85 90 90 87 NK NK NK NK NK NK
RACE (%)
White 65 68 60 68 68 69 84 84 77 78 77 84 84 82 77 78 78 NK NK NK NK NK NK
Black or African 9 8 7 4 6 4 7 7 9 9 9 7 7 7 6 6 6 NK NK NK NK NK NK
American
Asian 20 19 25 26 24 25 2 2 12 11 11 8 7 9 17 16 16 NK NK NK NK NK NK

SUSTAIN5 only abstracts available, thus baseline characteristics cannot be obtained. HbA1C, glycosylated hemoglobin; BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, modification of diet in renal disease;
SEM, semaglutide; PLA, placebo; EXER, exenatide release; GLA, insulin glargine; DUL, dulaglutide; SIT sitagliptin; OAD, oral antidiabetic drug; AHA, antihyperglycaemic agent; MET, metformin; TZD, thiazolidinediones; SU, sulfonylureas;
DE, diet and exercise; N/A, not applicable; NK, not known.

June 2018 | Volume 9 | Article 576

Efficacy and Safety of Semaglutide in Type 2 Diabetes
Shi et al. Efficacy and Safety of Semaglutide in Type 2 Diabetes

FIGURE 2 | Continued

Frontiers in Pharmacology | www.frontiersin.org 6 June 2018 | Volume 9 | Article 576

Shi et al. Efficacy and Safety of Semaglutide in Type 2 Diabetes

FIGURE 2 | Continued

Frontiers in Pharmacology | www.frontiersin.org 7 June 2018 | Volume 9 | Article 576

Shi et al. Efficacy and Safety of Semaglutide in Type 2 Diabetes

FIGURE 2 | Forest plots for the changes of HbA1C%, FPG, SMPG mean, SMPG Postprandial increment, body weight, BMI, Waist circumference, DBP, SBP, Pulse
rate between semaglutide treated and control treated patients with T2DM (A–C). Glycemic control indicators including HbA1C%, FPG, SMPG mean, SMPG
Postprandial increment etc. significantly decreased between semaglutide treated and control group (P < 0.001) (A). Body weight, BMI, Waist circumference also
decreased through semaglutide vs. control group (P < 0.001) (B). For blood pressure indicators, SBP and Pulse rate have significantly difference between
semaglutide and control group (P < 0.001), While difference of DBP is not significant (P = 0.113), in which semaglutide decrease SBP but increase pulse rate (C).
HbA1C, glycosylated hemoglobin; FPG, fasting plasma glucose; SMPG, self-monitoring of plasma glucose; BMI, body mass index; DBP, diastolic blood pressure;
SBP, systolic blood pressure.

Frontiers in Pharmacology | www.frontiersin.org 8 June 2018 | Volume 9 | Article 576

 Shi et al.

TABLE 2 | Relative risk of adverse events reported for semaglutide in comparison with control.

No. of studies Semaglutide therapy Control therapy Total RR (SEM/CON) 95% CI (P value) Homogeneity

I2 (%) P

ALL ADVERSE EVENTS

Adverse events 9 4199/5774 (72.7%) 3027/3999 (75.6%) 7226/9773 (73.9%) 1.04 0.99 to 1.09 (0.002) 66.5 0.147
Serious adverse events 9 815/5774 (14.1%) 768/3999 (19.2%) 1583/9773 (16.1%) 0.93 0.86 to 1.01 (0.54) 0 0.084
Fatal adverse events 6 45/3458 (1.3%) 26/1812 (1.4%) 71/5270 (1.3%) 0.90 0.56 to 1.47 (0.52) 0 0.678
Moderate adverse events 5 595/2858 (20.8%) 269/1214 (22.1%) 864/4072 (21.2%) 1.01 0.90 to 1.15 (0.97) 0 0.833

Frontiers in Pharmacology | www.frontiersin.org

Mild adverse events 5 1667/2858 (58.3%) 658/1214 (54.2%) 2325/4072 (57.0%) 1.08 0.96 to 1.22 (0.005) 73.1 0.194
AEs leading to discontinuation 9 507/5774 (8.7%) 199/3999 (4.9%) 706/9773 (7.2%) 2.07 1.58 to 2.73 (0.10) 39.5 < 0.001
ADVERSE EVENTS OCCURRING IN ≥ 5% PATIENTS BY PREFERRED TERM OR OTHER OF CLINICAL INTEREST
Gastrointestinal adverse events 7 2193/5107 (42.9%) 1026/3461 (29.6%) 3219/8568 (37.5%) 1.98 1.49 to 2.62 (<0.001) 92.3 < 0.001
Nausea 8 1002/5511 (18.1%) 330/3866 (8.5%) 1332/9377 (14.2%) 2.56 1.76 to 3.74 (<0.001) 84 < 0.001
Diarrhoea 8 772/5511 (14.0%) 353/3866 (9.1%) 1125/9377 (11.9%) 1.84 1.37 to 2.47 (0.001) 71.1 < 0.001
Constipation 6 218/3141 (6.9%) 64/1857 (3.4%) 282/4998 (5.6%) 2.07 1.28 to 3.35 (0.05) 54.4 0.003
Abdominal discomfort 2 41/685 (5.9%) 0/343 (0%) 41/1028 (3.9%) 18.94 2.60 to 137.73 (0.62) 0 0.004
Decreased appetite 6 253/3230 (7.8%) 73/2113 (3.4%) 326/5343 (6.1%) 3.30 1.44 to 7.61 (<0.001) 80.4 0.005
Vomiting 7 476/5306 (8.9%) 169/3763 (4.4%) 645/9069 (7.1%) 2.16 1.54 to 3.03 (0.02) 60.4 < 0.001

9
Cardiovascular system
Cardiovascular* 5 338/3656 (9.2%) 377/2830 (13.3%) 715/6486 (11.0%) 0.88 0.78 to 1.01 (0.71) 0 0.066
Lipase increased 7 293/3863 (7.5%) 137/2217 (6.1%) 430/6080 (7.0%) 1.36 0.93 to 2.00 (0.01) 62.5 0.113
Nervous system disorders 2 54/927 (5.8%) 25/463 (5.3%) 79/1390 (5.6%) 1.08 0.68 to 1.71 (0.81) 0 0.75
Headache 5 166/2661 (6.2%) 98/1737 (5.6%) 264/4398 (6.0%) 1.23 0.91 to 1.65 (0.27) 22.4 0.176
Other adverse events
Neoplasms 3 205/2946 (6.9%) 156/2176 (7.1%) 361/5122 (7.0%) 1.07 0.78 to1.46 (0.29) 18.6 0.673
Pancreatitis 5 15/4422 (0.3%) 12/2831 (0.4%) 27/7253 (0.3%) 0.82 0.36 to 1.88 (0.45) 0 0.641
Hypoglycaemia 5 411/3197 (12.8%) 367/2603 (14.0%) 778/5800 (13.4%) 1.07 0.94 to 1.21 (0.76) 0 0.317
Allergic reaction 2 114/2249 (5.0%) 124/2247 (5.5%) 238/4496 (5.2%) 0.92 0.72 to 1.78 (0.52) 0 0.51
Nasopharyngitis 7 424/3863 (10.9%) 239/2217 (10.7%) 663/6080 (10.9%) 0.86 0.74 to 0.99 (0.51) 0 0.04

Cardiovascular* means any events about cardiovascular or cardiac disorder, SEM, semaglutide; CON, control.

June 2018 | Volume 9 | Article 576

Efficacy and Safety of Semaglutide in Type 2 Diabetes
Shi et al.
P = 0.442) and SMPG (WMD: −0.31 mmol/L, 95% CI: −0.83
to 0.21, P = 0.249) with the comparison of insulin glargine.
With regards to body weight control by different treatment,
semaglutide was superior to all other therapies, including other
once weekly GLP-1 RAs (body weight, WMD: −3.19 kg, 95%
CI: 4.13 to 2.26, P < 0.001; BMI, WMD: −1.14 kg/m2 , 95% CI:
−1.47 to 0.81, P < 0.001; waist circumference, WMD: −2.33 cm,
95% CI: −2.86 to −1.81, P < 0.001). When regarding blood
pressure control by different treatment, most of the results were
in line with the primary analyses except for DBP as compared
to sitagliptin (WMD: −0.86 mmHg, 95% CI: −1.60 to −0.13,
P = 0.022) or other GLP-1 RAs (WMD: −1.04 mmHg, 95% CI:
−2.05 to−0.03, P = 0.044).
Considering the risk of AEs by different treatment, most
results were consistent with the primacy analyses, with the
exception of a mildly increased risk of any AEs when compared
with insulin glargine (RR: 1.10, 95% CI: 1.00 to 1.20, P = 0.040)
or other oral antidiabetic drugs (RR: 1.22, 95% CI: 1.08 to 1.37,
P = 0.001). Interestingly, semaglutide even slightly decreased the
risk of serious AEs as compared to placebo (RR: 0.91, 95% CI: 0.83
to 0.99, P = 0.030). With respect to GI AEs by different treatment,
no significantly increased risk was detected with semaglutide vs.
sitagliptin (RR: 3.21, 95% CI: 0.86 to 11.97, P = 0.082) or other
GLP-1 RAs (RR: 1.07, 95% CI: 0.94 to 1.23, P = 0.300).
The results of sensitivity analysis, as shown in Tables S5, S6,
were not altered after excluding each of the studies or placebo-
controlled studies.
Publication Bias
As shown in Figures S1A–C, visual inspection of funnel plots for
the analyses showed a certain dissymmetry. Further quantitative
analyses of Begg test and Egger test were performed to detect the
publication bias at level of statistics. Finally, quantitative analyses
failed to find the significant presence of publication bias except
for HbA1c% (P = 0.029 for Egger test), PSMPG (P < 0.05 for
both Begg test and Egger test), suggesting that publication bias
was acceptable overall. However, the presence of sponsored bias
was a concern because all included nine studies were sponsored
by Novio Nodisk.
DISCUSSION
This study was a meta-analysis to comprehensively evaluate
the efficacy and safety of once-weekly semaglutide, which
included nine controlled phase III clinical studies with different
comparators in patients with type 2 diabetes. Overall, the results
of our study suggested that semaglutide had a preferable property
of glycemic control, body weight control and blood pressure
control compared with other therapies (placebo, sitagliptin, other
GLP-1 RAs, insulin glargine, and other oral anti-diabetic drugs).
Meanwhile, semaglutide did not increase different degrees of
AEs, hypoglycemia, and pancreatitis, but induced a high risk of
gastrointestinal AEs. The results were consistent across the key
subgroups.
A meta-analysis on the focus of other GLP-1 RAs (dulaglutide,
albiglutide, and released exenatide) was performed by
Karagiannis T (Karagiannis and Liakos, 2015), which showed that
Frontiers in Pharmacology | www.frontiersin.org
Efficacy and Safety of Semaglutide in Type 2 Diabetes
other GLP-1 RAs can reduce HbA1c% by about 1% compared
with placebo and 0.3–0.4% compared with other anti-diabetic
drugs (Karagiannis and Liakos, 2015). Another meta-analysis
of dulaglutide showed a significantly reduced HbA1c% level
by 0.68% as compared to monotherapy (metformin and
liraglutide) and by 0.51% as compared to add-on therapy
(placebo, sitagliptin, exenatide, liraglutide, and glargine; Zhang
et al., 2016). Our results revealed that semaglutide significantly
reduced the value of HbA1c% by 0.93%, FPG by 1.15 mmol/L,
SMPG by 1.19 mmol/L and PSMPG by 0.43 mmol/L when
compared with other therapies. In a dose-finding study,
semaglutide revealed a dose-dependent effects on the level of
HbA1c% (Nauck et al., 2016). Of note, two up-to-date studies
showed that semaglutide had a preferable property on glycemic
control than other once-weekly GLP-1 RAs (released exenatide
and dulaglutide) (Ahmann et al., 2018; Pratley et al., 2018).
Semaglutide at the dosage of 1.0 mg can reduce mean HbA1c%
by 1.5%, but released exenatide with the dosage of 2.0 mg can
only reduce HbA1c% by 0.9%. Thus, the estimated treatment
difference of semaglutide vs. released exenatide was −0.62%
with HbA1c% and −0.84 mmol/L with FPG (Ahmann et al.,
2018). Similarly, semaglutide was superior to dulaglutide by the
reduction of HbA1c% about 0.40% regardless of low dosage or
high dosage (Pratley et al., 2018). Several underline mechanisms
might explain the reason of strongly hypoglycemic ability of
semaglutide. Firstly, the short-acting GLP-1 RAs primarily lower
postprandial plasma glucose by inhibiting gastric emptying,
whereas long-acting GLP-1 RAs have a strong effects on FPG
through mediating insulinotropic and glucagonostatic actions
(Meier, 2012). In addition, semaglutide have the capacity to
improve beta cell function and insulin sensitivity primarily via
weight loss (Fonseca et al., 2017; Kapitza et al., 2017). A positive
effect on insulin sensitivity and beta cell function might have
also contributed to the improvement in glycaemic control with
semaglutide vs. other anti-diabetic agents.
Cardiovascular diseases are the leading cause of premature
mortality and disability accounting for nearly one third of all
deaths worldwide with considerable impacts on body weight
and hypertension (Sisti et al., 2017). As for body weight
control, weight loss was observed across all the GLP-1 RAs.
A network meta-analysis evaluating the ability of body weight
reduction have demonstrated that the rank 1 was exenatide
10 µg twice daily (reduced 1.92 kg than placebo) and rank 2
was liraglutide 1.8 mg daily (reduced 0.98 kg than placebo) (Sun
et al., 2015a). Furthermore, semaglutide lowered body weight
more than liraglutide (−4.8 kg for semaglutide 1.6 mg/day vs.
−2.6 kg for liraglutide 1.8 mg; Nauck et al., 2016). However,
both albiglutide and dulaglutide had showed fewer efficacies
than liraglutide in the matter of weight loss. For albiglutide,
weight loss was 0.6 kg but 2.2 kg for liraglutide in a 26 week trial
(Pratley et al., 2014). For dulaglutide, weight loss was 2.9 kg but
3.6 kg for liraglutide in another 26 weeks trial (Dungan et al.,
2014). In this meta-analysis, semaglutide significantly reduced
body weight of 3.47 kg when compared with other therapies.
Further subgroup analysis also found that semaglutide lowered
body weight much more efficacious than other GLP-1 RAs
(−3.19 kg).
10 June 2018 | Volume 9 | Article 576
Shi et al.
With respect to blood pressure control, the magnitude of SBP
reduction was observed for all GLP-1 RAs. A previous study
had shown that the reduction of nearly 5 mmHg of SBP was
supposed to lower risk of major cardiovascular events and death
(Patel et al., 2007). Another meta-analysis had demonstrated
that all GLP-1 RAs could decrease SBP ranging from 1.84
mmHg to 4.60 mmHg, while only exenatide (10 µg twice
daily) significantly reduced DBP by 1.08 mmHg (Sun et al.,
2015c). In addition, both exenatide and liraglutide could increase
heart rate by 2–3 beats/min (Sun et al., 2015c). In the present
study, semaglutide could reduce SBP by 2.55 mmHg when
compared with other therapies. Consistent with other GLP-1
RAs, an increased pulse rate of 2.21beats/min was observed in
the semaglutide treatment. In a cardiovascular outcomes trial,
patients receiving semaglutide had a significant 26% decreased
risk of death on cardiovascular causes, nonfatal myocardial
infarction, or nonfatal stroke than those receiving placebo (Marso
et al., 2016). The underlying mechanism on this association
remains unclear. Diabetes itself is associated with an increased
risk of cardiovascular disease, and well-controlled blood glucose
with semaglutide therapy may contribute to low cardiovascular
events. Regarding increased pulse rate, it is a class effect of GLP-1
RAs. The possible mechanism of increased heart rate of GLP-
1 RAs is related to the activate effect on myocytes in sinoatrial
node or the sympathetic nervous system (Lorenz et al., 2017).
However, it is of note that the increased heart rate was not
associated with increased cardiovascular risks in previous studies
(Tan et al., 2017).
Consistent with other GLP-1 RAs, semaglutide did not
increase any AEs, fatal, moderate, and mild AEs (Karagiannis
and Liakos, 2015; Zhang et al., 2016). The most commonly
reported AEs with semaglutide were gastrointestinal disorders,
mainly manifested as nausea, vomiting and diarrhea, abdominal
discomfort, and decreased appetite. Generally, the majority of
gastrointestinal events were mild or moderate in severity. When
compared with other GLP-1RAs, semaglutide did not increase
gastrointestinal events (RR: 1.07, 95%CI: 0.94 to 1.23, P = 0.3).
Furthermore, the risk of AEs leading to premature treatment
discontinuation was much higher in semaglutide than other
therapies (RR: 2.07, 95%CI: 1.58 to 2.73, P < 0.001), and
the most reasons were still gastrointestinal events. A previous
meta-analysis had revealed that all GLP-1 RAs dose regimens
significantly increased the incidence of gastrointestinal events
(Sun et al., 2015b). Indeed, gastrointestinal effects are a class effect
of GLP-1 RAs, and most patients can tolerate. The proportion
of patients withdrawing from study due to treatment-emergent
AEs (TEAEs) was increased with the incremental dosage of
semaglutide (Sun et al., 2015b; Nauck et al., 2016). Thus, for those
who did not tolerate semaglutide, a low dose initiation may be
an optional choice. The possible mechanism of gastrointestinal
events of GLP-1 RAs are as follows: (1) there is a strong
relationship in the GLP-1 RAs class that short-acting GLP-1
RAs display a prominent ability to reduce gastric emptying,
nevertheless long-acting GLP-1 RAs have better glycemic control
ability and less effect on gastric emptying (Lau et al., 2015); (2)
Enhanced GLP-1 concentration mediated the anorexigenic effect
in the paraventricular hypothalamus (Liu et al., 2017).
Frontiers in Pharmacology | www.frontiersin.org
Efficacy and Safety of Semaglutide in Type 2 Diabetes
Otherwise, hypoglycemia is a serious challenge and obstacle in
the T2DM treatment. In this meta-analysis, semaglutide did not
increase the risk of hypoglycemia as compared to other therapies
(RR: 1.07, 95% CI: 0.94 to 1.21, P = 0.317), which was consistent
with the findings in a recently published meta-analysis (Zhang
et al., 2016).
There has been remaining controversial on the risk of
pancreatitis caused by incretin-based drugs (Butler et al., 2013).
Some early studies did not support an increased risk of
pancreatitis in incretin-treated patients with T2DM, while other
studies did agree that incretin-based therapies may associate
with pancreatitis (Li et al., 2014; Monami et al., 2014; Giorda
et al., 2015; Roshanov and Dennis, 2015). In this meta-analysis,
no significantly higher risk was observed with semaglutide vs.
other therapies (0.3% vs. 0.4%; RR: 0.82, 95% CI: 0.36 to 1.88,
P = 0.641).
Interestingly, this study demonstrated that semaglutide
slightly decreased the risk of nasopharyngitis (RR: 0.86, 95%CI:
0.74 to 0.99, P = 0.04). This is a controversial conclusion at
present, and the mechanism is still unclear. The possible reason
that GLP-1 can inhibit infiltration and inflammation in adipose
tissue macrophage may explain this finding partly (Lee et al.,
2012).
Accordingly, semaglutide might become an alternative in
T2DM patients under several clinical scenarios, such as patients
who are intolerant to metformin or other hypoglycemic agent,
patients with overweight or hypertension, patients who exist
obvious insulin resistance, and patients with cardiovascular high-
risk factors.
This study had several limitations. Firstly, there were only 9
RCTs included in this meta-analysis, of which SUSTAIN 5 were
only abstract that some data cannot be extracted. We also have
not get access to the compliance data due to the exclusion of real-
world studies, making powerful subgroup analysis unavailable.
Secondly, several outcomes have heterogeneity in spite of the
performance of subgroup and sensitivity analysis. Thirdly, the
baseline characteristics of included studies were not the same,
including background treatment, controls, dosage, and duration
of follow up. Whereas, we have performed the corresponding
subgroup analysis to assess potential effect modifiers in
baseline characteristics, and the results failed to identify these
potential confounding on the outcomes. Undeniably, residual
confounding effects between included studies cannot be excluded
absolutely. Otherwise, the duration of included studies was
different, which may lead to certain bias. Finally, it must be
admitted that these studies of semaglutide are all sponsored
by Novio Nodisk, thus sponsorship bias may present in this
study.
CONCLUSION
Our meta-analysis illustrated that semaglutide could improve
the control of blood glucose, body weight and blood pressure
and did not increase the risk of hypoglycemia and pancreatitis.
Overall, semaglutide was effective and acceptable in patients
with T2DM except for a high risk of gastrointestinal disorders.
11 June 2018 | Volume 9 | Article 576
Shi et al.
The capacity of glycaemic control and body weight control of
semaglutide appeared more effective than other GLP-1 receptor
agonists. However, considering the number of included studies
and potential limitations, more large-scale, well-designed RCT,
real-world studies as well as HRQOL studies are needed to prove
our findings.
AUTHOR CONTRIBUTIONS
F-HS and HL exacted and analyzed the data and wrote the
first draft of the protocol. MC helped with the design of
the protocol. Z-LZ submitted the registration on PROSPERO.
Z-CG revised the manuscript. X-YL is the guarantors for
the publication and take the responsibility for the paper.
All authors participated in read, and approved the final
manuscript.
REFERENCES
Ahmann, A. J., Capehorn, M., Charpentier, G., Dotta, F., Henkel, E., and Lingvay,
I. (2018). Efficacy and safety of once-weekly semaglutide versus exenatide ER in
subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized
clinical trial. Diabetes Care 41, 258–266. doi: 10.2337/dc17-0417
Ahrén, B., Masmiquel, L., Kumar, H., Sargin, M., Karsbøl, J. D., Jacobsen,
S. H., et al. (2017). Efficacy and safety of once-weekly semaglutide versus
once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or
both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-
blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 5, 341–354.
doi: 10.1016/S2213-8587(17)30092-X
Aroda, V. R., Bain, S. C., Cariou, B., Piletic, M., Rose, L., Axelsen, M., et al.
(2017). Efficacy and safety of once-weekly semaglutide versus once-daily
insulin glargine as add-on to metformin (with or without sulfonylureas) in
insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-
label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes
Endocrinol. 5, 355–366. doi: 10.1016/S2213-8587(17)30085-2
Butler, P. C., Elashoff, M., Elashoff, R., and Gale, E. A. M. (2013). A critical analysis
of the clinical use of incretin-based therapies: are the GLP-1 therapies safe?
Diabetes Care 36, 2118–2125. doi: 10.2337/dc12-2713
Chen, Y. H., Lin, H., Xie, C. L., Hou, J. W., and Li, Y. G. (2017).
Role of adenosine-guided pulmonary vein isolation in patients undergoing
catheter ablation for atrial fibrillation: a meta-analysis. Europace 19, 552–559.
doi: 10.1093/europace/euw201
Conway, R., Rodbard, H., Lingvay, I., Reed, J., Rosa, R. D., Rose, L., et al. (2016).
Efficacy and safety of semaglutide once-weekly vs. placebo as add-on to basal
insulin alone or in combination with metformin in subjects with type 2 diabetes
(SUSTAIN 5). Can. J. Diabetes 40, S41–S42. doi: 10.1016/j.jcjd.2016.08.116
Dhillon, S. (2018). Semaglutide: first global approval. Drugs 78, 275–284.
doi: 10.1007/s40265-018-0871-0
Doggrell, S. A. (2018). Sgemaglutide in type 2 diabetes - is it the best glucagon-like
peptide 1 receptor agonist (GLP-1R agonist)? Expert Opin. Drug Metab. Toxicol.
14, 371–377. doi: 10.1080/17425255.2018.1441286
Dugan, J. A. (2017). Standards of care and treatment in diabetes. Phys. Assist. Clin.
2, 13–23. doi: 10.1016/j.cpha.2016.08.004
Dungan, K. M., Povedano, S. T., Forst, T., González, J. G., Atisso, C., Sealls,
W., et al. (2014). Once-weekly dulaglutide versus once-daily liraglutide
in metformin-treated patients with type 2 diabetes (AWARD-6): a
randomised, open-label, phase 3, non-inferiority trial. Lancet 384, 1349–1357.
doi: 10.1016/S0140-6736(14)60976-4
Egger, M., Davey Smith, G., Schneider, M., and Minder, C. (1997). Bias
in meta-analysis detected by a simple, graphical test. BMJ 315, 629–634.
doi: 10.1136/bmj.315.7109.629
Frontiers in Pharmacology | www.frontiersin.org
Efficacy and Safety of Semaglutide in Type 2 Diabetes
FUNDING
This article is supported by the Fundamental Research Funds
for the Central Universities (No.17JCYB11), the pharmaceutical
fund of college of medicine, Shanghai Jiaotong University
(No.JDYX2017QN003), the fund of Shanghai Pharmaceutical
Association (No.2015-YY-01-20), Program for Key Discipline of
Clinical Pharmacy of Shanghai (2016-40044-002), and Program
for Key but Weak Discipline of Shanghai Municipal Commission
of Health and Family Planning (2016ZB0304).
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fphar.
2018.00576/full#supplementary-material
Fonseca, V., Capehorn, M., Garg, S., Jodar, E., Birch, S., Holst, A. G., et al. (2017).
Semaglutide-induced reductions in insulin resistance are mediated primarily
via weight loss in subjects with type 2 diabetes (SUSTAIN 1-3). Diabetologia
60, S375–S376.
Giorda, C. B., Sacerdote, C., Nada, E., Marafetti, L., Baldi, I., and Gnavi, R.
(2015). Incretin-based therapies and acute pancreatitis risk: a systematic
review and meta-analysis of observational studies. Endocrine 48, 461–471.
doi: 10.1007/s12020-014-0386-8
Higgins, J. P., Altman, D. G., Gøtzsche, P. C., Jüni, P., Moher, D., Oxman, A. D.,
et al. (2011). The Cochrane Collaboration’s tool for assessing risk of bias in
randomised trials. BMJ 343:d5928. doi: 10.1136/bmj.d5928
Inzucchi, S. E., Bergenstal, R. M., Buse, J. B., Diamant, M., Ferrannini, E., Nauck,
M., et al. (2012). Management of hyperglycemia in type 2 diabetes: a patient-
centered approach: position statement of the American Diabetes Association
(ADA) and the European Association for the Study of Diabetes (EASD).
Diabetes Care 35, 1364–1379. doi: 10.2337/dc12-0413
Inzucchi, S. E., Bergenstal, R. M., Buse, J. B., Diamant, M., Ferrannini, E., Nauck,
M., et al. (2015). Management of hyperglycemia in type 2 diabetes, 2015: a
patient-centered approach: update to a position statement of the American
Diabetes Association and the European Association for the Study of Diabetes.
Diabetes Care 38, 140–149. doi: 10.2337/dc14-2441
Jaïs, X., D’Armini, A. M., Jansa, P., Torbicki, A., Delcroix, M., Ghofrani,
H. A., et al. (2008). Bosentan for treatment of inoperable chronic
thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in
iNopErable forms of chronIc Thromboembolic pulmonary hypertension), a
randomized, placebo-controlled trial. J. Am. Coll. Cardiol. 52, 2127–2134.
doi: 10.1016/j.jacc.2008.08.059
Kaku, K., Yamada, Y., Watada, H., Abiko, A., Nishida, T., Zacho, J., et al.
(2018). Safety and efficacy of once-weekly semaglutide vs additional oral
antidiabetic drugs in Japanese people with inadequately controlled type
2 diabetes: a randomized trial. Diabetes Obes. Metab. 20, 1202–1212.
doi: 10.1111/dom.13218
Kapitza, C., Dahl, K., Jacobsen, J. B., Axelsen, M. B., and Flint, A. (2017).
Effects of semaglutide on beta cell function and glycaemic control in
participants with type 2 diabetes: a randomised, double-blind, placebo-
controlled trial. Diabetologia 60, 1390–1399. doi: 10.1007/s00125-017-
4289-0
Kapitza, C., Nosek, L., Jensen, L., Hartvig, H., Jensen, C. B., and Flint,
A. (2015). Semaglutide, a once-weekly human GLP-1 analog, does
not reduce the bioavailability of the combined oral contraceptive,
ethinylestradiol/levonorgestrel. J. Clin. Pharmacol. 55, 497–504.
doi: 10.1002/jcph.443
Karagiannis, T., and Liakos, A. (2015). Efficacy and safety of once-weekly
glucagon-like peptide 1 receptor agonists for the management of type 2
12 June 2018 | Volume 9 | Article 576
Shi et al.
diabetes: a systematic review and meta-analysis of randomized controlled trials.
Diabetes Obes. Metab. 17, 1065–1074. doi: 10.1111/dom.12541
Koro, C. E., Bowlin, S. J., Bourgeois, N., and Fedder, D. O. (2004). Glycemic
control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a
preliminary report. Diabetes Care 27, 17–20. doi: 10.2337/diacare.27.1.17
Lau, J., Bloch, P., Schäffer, L., Pettersson, I., Spetzler, J., Kofoed, J., et al. (2015).
Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue
semaglutide. J. Med. Chem. 58, 7370–7380. doi: 10.1021/acs.jmedchem.5b
00726
Lee, Y. S., Park, M. S., Choung, J. S., Kim, S. S., Oh, H. H., Choi, C. S., et al.
(2012). Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration
and inflammation in an obese mouse model of diabetes. Diabetologia 55,
2456–2468. doi: 10.1007/s00125-012-2592-3
Li, L., Shen, J., Bala, M. M., Busse, J. W., Ebrahim, S., Vandvik, P. O.,
et al. (2014). Incretin treatment and risk of pancreatitis in patients
with type 2 diabetes mellitus: systematic review and meta-analysis of
randomised and non-randomised studies. BMJ 348:g2366. doi: 10.1136/
bmj.g2366
Liu, J., Conde, K., Zhang, P., Lilascharoen, V., Xu, Z., Lim, B. K., et al. (2017).
Enhanced AMPA receptor trafficking mediates the anorexigenic effect of
endogenous glucagon-like peptide-1 in the paraventricular Hypothalamus.
Neuron 96, 897.e895–909.e895. doi: 10.1016/j.neuron.2017.09.042
Lorenz, M., Lawson, F., Owens, D., Raccah, D., Roy-Duval, C., Lehmann, A., et al.
(2017). Differential effects of glucagon-like peptide-1 receptor agonists on heart
rate. Cardiovasc. Diabetol. 16:6. doi: 10.1186/s12933-016-0490-6
Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter, L. A.,
et al. (2016). Semaglutide and cardiovascular outcomes in patients with type 2
diabetes. N. Engl. J. Med. 375, 1834–1844. doi: 10.1056/NEJMoa1607141
Meier, J. J. (2012). GLP-1 receptor agonists for individualized treatment
of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728–742.
doi: 10.1038/nrendo.2012.140
Moher, D., Liberati, A., Tetzlaff, J., and Altman, D. G. (2010). Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA statement. Int. J.
Surg. 8, 336–341. doi: 10.1016/j.ijsu.2010.02.007
Monami, M., Dicembrini, I., Nardini, C., Fiordelli, I., and Mannucci, E.
(2014). Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-
analysis of randomized clinical trials. Diabetes Res. Clin. Pract. 103, 269–275.
doi: 10.1016/j.diabres.2014.01.010
Nauck, M. A., Petrie, J. R., Sesti, G., Mannucci, E., Courrèges, J. P., Lindegaard, M.
L., et al. (2016). A phase 2, randomized, dose-finding study of the novel once-
weekly human GLP-1 analog, semaglutide, compared with placebo and open-
label liraglutide in patients with type 2 diabetes. Diabetes Care 39, 231–241.
doi: 10.2337/dc15-0165
Patel, A., MacMahon, S., Chalmers, J., Neal, B., Woodward, M. et al.
(2007). Effects of a fixed combination of perindopril and indapamide
on macrovascular and microvascular outcomes in patients with
type 2 diabetes mellitus (the ADVANCE trial): a randomised
controlled trial. Lancet 370, 829–840. doi: 10.1016/S0140-6736(07)
61303-8
Pratley, R. E., Aroda, V. R., Lingvay, I., Lüdemann, J., Andreassen, C., Navarria,
A., et al. (2018). Semaglutide versus dulaglutide once weekly in patients with
type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet
Diabetes Endocrinol. 6, 275–286. doi: 10.1016/S2213-8587(18)30024-X
Pratley, R. E., Nauck, M. A., Barnett, A. H., Feinglos, M. N., Ovalle, F.,
Harman-Boehm, I., et al. (2014). Once-weekly albiglutide versus once-
daily liraglutide in patients with type 2 diabetes inadequately controlled
Frontiers in Pharmacology | www.frontiersin.org
Efficacy and Safety of Semaglutide in Type 2 Diabetes
on oral drugs (HARMONY 7): a randomised, open-label, multicentre,
non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2, 289–297.
doi: 10.1016/S2213-8587(13)70214-6
Roshanov, P. S., and Dennis, B. B. (2015). Incretin-based therapies are associated
with acute pancreatitis: meta-analysis of large randomized controlled trials.
Diabetes Res. Clin. Pract. 110, e13–e17. doi: 10.1016/j.diabres.2015.10.014
Seino, Y., Terauchi, Y., Osonoi, T., Yabe, D., Abe, N., Nishida, T., et al. (2018).
Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as
monotherapy in Japanese people with type 2 diabetes. Diabetes Obes. Metab. 20,
378–388. doi: 10.1111/dom.13082
Sisti, L. G., Dajko, M., Campanella, P., Shkurti, E., Ricciardi, W., and de
Waure, C. (2017). The effect of multifactorial lifestyle interventions on
cardiovascular risk factors: a systematic review and meta-analysis of trials
conducted in the general population and high risk groups. Prev. Med. 109,
82–97. doi: 10.1016/j.ypmed.2017.12.027
Sorli, C., Harashima, S. I., Tsoukas, G. M., Unger, J., Karsbøl, J. D., Hansen, T.,
et al. (2017). Efficacy and safety of once-weekly semaglutide monotherapy
versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-
blind, randomised, placebo-controlled, parallel-group, multinational,
multicentre phase 3a trial. Lancet Diabetes Endocrinol. 5, 251–260.
doi: 10.1016/S2213-8587(17)30013-X
Sun, F., Chai, S., Li, L., Yu, K., Yang, Z., Wu, S., et al. (2015a). Effects of glucagon-
like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes:
a systematic review and network meta-analysis. J. Diabetes Res. 2015:157201.
doi: 10.1155/2015/157201
Sun, F., Chai, S., Yu, K., Quan, X., Yang, Z., Wu, S., et al. (2015b). Gastrointestinal
adverse events of glucagon-like peptide-1 receptor agonists in patients with type
2 diabetes: a systematic review and network meta-analysis. Diabetes Technol.
Ther. 17, 35–42. doi: 10.1089/dia.2014.0188
Sun, F., Wu, S., Guo, S., Yu, K., Yang, Z., Li, L., et al. (2015c). Impact of GLP-
1 receptor agonists on blood pressure, heart rate and hypertension among
patients with type 2 diabetes: a systematic review and network meta-analysis.
Diabetes Res. Clin. Pract. 110, 26–37. doi: 10.1016/j.diabres.2015.07.015
Tan, X., Cao, X., Zhou, M., Zou, P., and Hu, J. (2017). Efficacy and safety of once-
weekly semaglutide for the treatment of type 2 diabetes. Expert Opin. Investig.
Drugs 26, 1083–1089. doi: 10.1080/13543784.2017.1360274
Turner, R. C., Cull, C. A., Frighi, V., and Holman, R. R. (1999). Glycemic
control with diet, sulfonylurea, metformin, or insulin in patients with type
2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS
49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 281, 2005–2012.
doi: 10.1001/jama.281.21.2005
Zhang, L., Zhang, M., Zhang, Y., and Tong, N. (2016). Efficacy and safety of
dulaglutide in patients with type 2 diabetes: a meta-analysis and systematic
review. Sci. Rep. 6:18904. doi: 10.1038/srep18904
Conflict of Interest Statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Copyright © 2018 Shi, Li, Cui, Zhang, Gu and Liu. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC
BY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) and the copyright owner are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these
terms.
13 June 2018 | Volume 9 | Article 576